1-loweralkanoyl-3-(2-substituted ethyl)indoles



United States Patent 3,489,429 1-LOWERALKANOYL-3-(2-SUBSTITUTED ETHYL)INDOLES David R. Herbst, King of Prussia, Pa., assignor to American HomeProducts Corporation, New York, N.Y., a corporation of Delaware NoDrawing. Application Jan. 18, 1966, Ser. No. 521,431, which is acontinuation-in-part of application Ser. No. 383,971, July 20, 1964.Divided and this application Dec. 18, 1967, Ser. No. 720,424

Int. Cl. C07d 57/00, 27/56; A61k 27/00 US. Cl. 260-e-326.15 2 ClaimsABSTRACT OF THE DISCLOSURE This invention relates to compounds of theformula wherein R is a substituted amino group and R is lower alkanoyl,which possess central nervous system, hypotensive and hypoglycemicactivity.

wherein R is selected from the group consisting of diloweralkylamino,pyrrolidinyl, piperidino and morpholino and R is selected from the groupconsisting of lower alkanoyl.

The new compounds of the present invention are prepared by firsttreating a solution of a selected indole of the following structure:

wherein R has the value previously ascribed in an inert solvent such asdimethylformamide or toluene with either an alkali metal hydride or analkali metal amide at a temperature in the range of about 25 C. to about110 C. for a period of about 1 to about 5 hours. Thereafter, analkanoyl, halide is added to the reaction mixture at a reactiontemperature from about 25 C. to about C. for a period of from about 12to about 18 hours, preferably about 16 hours. The reaction mass is thenextracted with either dilute aqueous hydrochloric acid or lbenzene toprovide a crude product which may be thereafter purified according toconventional procedures such as by chromatography.

The l-substituted bases obtained according to the foregoing reaction arethen convertible to their acid salts such as the hydrochloric acid saltsby treating an ethereal solution of the free base with either gaseous orisopropanolic hydrogen chloride. Other acid salts may also be preparedby treating the free :base form of the compounds described with otheracceptable organic or inorganic acids. Suitable acids for this purposeinclude hydrobromic, sulfuric, phosphoric, nitric, benzoic,methylsulfonic, p-tolylsulfonic, benzenesulfonic, naphthalenesulfonic,salicylic, glycolic, acetic, maleic, succinic, tartaric, stearic,palmitic, citric, glutaric, lactic and the like.

The starting indoles generally identified by formula B above are knownor are prepared by methods such as that disclosed by M. E. Specter andW. C. Anthony, US. Patent 2,870,162 (Jan. 20, 1959) and T. Vitali and F.Massini, Boll. Sci. Fac. Chim. Ind. Bologna, 17, 84-7 (1959) [C.A., 54,19644b(1960)].

The new compounds of the present invention encompassed within thosedefined by the Formula A above possess quite unexpectedly, valuablepharmaceutical properties. In particular the new compounds of thepresent invention possess central nervous system activity and inaddition possess hypotensive and hypoglycemic activity. These newcompounds are therefore useful for such purposes. I

When used for the purposes described above, it may be desirableaccording to conventional pharmaceutical practice to combine thespecific compound identified into compositions suitable for enteral orparenteral administration by combining the same with a pharmaceuticallyadministrable organic or inorganic carrier. The composition may beprepared in solid form, such as in tablets or in liquid form such as asolution, suspension or emulsion. Suitable liquid carriers includewater, gelatin, lactose, starch, talc, vegetable oils, alcohols,polyalcohols, gums, USP syrups and the like. The pharmaceuticalcomposition in addition to the active principle and the carrier mayinclude auxiliary materials such as coloring, stabilizing, wetting oremulsifying agents. It is of course recognized as essential that thecarrier as well as any other materials present with the active principlebe inert with respect thereto.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame eifect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford efiective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about mg. to about 400 mg. per day,although as aforementioned variations will occur. However, a dosagelevel that is in the range of from about 20 mg. to about 200 mg. per dayis most desirably employed in order to achieve effective results.

Reference now to the specific examples which follow will provide abetter understanding of the new compounds of the present invention aswell as of the method by which the same can ibe prepared. In theseexamples hereinafter, the starting indole used may be identified forconvenience by numerals I-IV. The numerals represent the followingcompounds, (I) 3-[2-(1-pyrrolidinyl)ethyl] indole, (II)3-(2-diethylaminoethyl) indole, (III) 3-(2-piperidinoethyl) indole and(IV) 3-(2-morpholinoethyl) indole.

EXAMPLE I A solution of 8.65 g. 3-(Z-diethylaminoethyl)indole (II) in200 ml. dry dimethylformamide (DMF) is stirred with 2.30 g. ca. 50%sodium hydride/mineral oil dispersion for one hour, 6.74 g. (5.53 ml.)benzoyl chloride in ml. DMF is added dropwise and the mixture is stirredat ca. 25 C. for 16 hours. Dissolution of the reaction mixture inbenzene, washing of the organic solution with dilute, aqueous potassiumbicarbonate solution, and then with brine, and distillation of thesolvent gives an oily base. The oil is dissolved in ca. ml. of 1:1benzene/ n-hexane and is chromatographically purified on a column of 250g. neutral, activity III alumina. The base is eluted with 1:1benzene-n-hexane and is dissolved in anhydrous ether and is treated withexcess isopropanolic hydrogen chloride. Crystallization (twice) of thesalt from acetoneethyl acetate gives 1-benzoyl-3-(2-diethylaminoethyl)indole, hydrochloride dec. 146.5148.5,

A different modification of XIV, dec. 133.0135.5 may be isolated.

In the same manner, the following are prepared by utilizing theappropriate indole starting material and the selected reactantidentified:

TABLE I a KBr EtOH Reactant Dec. pt., C. Crystalhzmg Solvent XML, ,u Amax, (my) a Product:

VII p-CI-I OCGH OOCI 187-189 Acetone 3. 95, 4. 11 259-265 24,350 5. 99295-310 11, 290

VIII CGH5SO2C1 193. 5495.0 Acetone 22,0125 253-259 12,340 .5 280-295 4,290 IX pC1CsH SO Cl 192-194 Acetone-ethylacetate.- :93, 249-258 15,220280-294 6,150

3.93 I 224 34,600 XI CBHBCHQC]. 186-188 Acetone 285-292 7,010 4 295-2996, 310

XV p-ClCdLCO Cl 170-172 do 253.5 25,100 301-310 7, 820

XVI p-CH OC6H COCl 2 139. 5-141. 5 Acetone isopropanol 4. 22 259-26524,050 5. 97 296-309 11, 310

XVII 0012580201 191-193 do 3. 255 12,620 7. 280-294 4, 250

VXIII p-ClC5H4SOzC1 190. 0-192. 5 Acetone g5, 11 254 14,960 .52 281-2955,520

XIX p-CH OnH4SO2Cl 183-186 do 18 249-258 12,820 ,8. 55 281-294 5,090

4. 16 224 34, 600 XX CBH CH2OI -152 Acetone, isopropanoL gag-292 ,780-298 6,090

XXVI p-CH3CsH4COCl 3 211. 5-213.0 do 33, 4. 09 254 23,500 l 306 7,250

3.80, 3.95 241 19, 410 XXVII S 0001 3 234-236 Isopropanol 3. 80, 3. 95293 6, 460 301 7,

3. 82, 3. 97 239. 5 19, 000 XXVIII (CH;) OH(GH2)2COCl Soft. 153, 158-160Acetone 4. 17, 5.91 292 6,710 300. 5 7, 270

250-257 19,860 XXIX p-OH OCGH4SO Gl 184-186 do 279-283 6,880 288-2925,710

XXX p-CH3CaH4COCl 139. 5-143.0 -do 32, 4.20 253-259 22,230 305-311 6,460

3. 98-4. 13 240 19, 700 XXXI S COC1 152. 5154.5 do 5.89 292.5 6,310 3017,100

3. 97, 4. 09 240 19, 260 XXXII (CH;)2CH(CH2)2COCl 177.5178.5 do 5.92 2926,950 301 7, 600

4. 21, 7. 33 252-256 19, 210 XXXIII p-CH3OCOH4SO2C1 1735-1755 do 8.58321-3132 6,140 9- 5,150

Gaseous instead of isopropanolic hydrogen chloride is used to generatethe salt. This is a melting point rather than a decomposition point.

2 Crystallization from acetone affords a modification dec. 157-159 C.

8 This is a melting point.

EXAMPLE II A mixture of 3.22 g. (I), 70 ml. dry DMF and 0.86 g.

6. bicarbonate solution instead of potassium carbonate solution, andgaseous hydrogen chloride is used to generate the salt.

TABLE III KBr 95% EtOH Reaetant M.P., C. Crystallizmg Solvent M1520)kmnfimu) e Product:

V 11 0001 244. 5-247. 5 Ethanol 3. 97, 4.14 251. 5 21, 500 6.97 303 7,380 X p-CH C H SOzCl (Soit 192) 195-199 Acetone .2 3. 93, 4. 25 250-25812, 520 7. 39, 8. 58 279-295 5, 400 3. 94, 413 223 43, 500 XIIp-C1C0H4CHgC1 192. 5-l95.0 ----.d0 276-291 7,200 293-296 6, 580 12 222.5 42, 300 XXI p-CiC H CH O1 2 127-129 Acetone-ethyl acetate 278-290 8,550 294-298 7, 590

l The potassium bicarbonate wash is omitted.

2 This is a decomposition point. ca. 50% sodium hydride/mineral oildispersion is stirred 1 hour, at ca. 25 C. and 3.15 g. p-chlorobenzoylchloride is added dropwise. After stirring 17 hours at ca. 25 C., thesolvent is distilled and the residue is treated with dilute aqueouspotassium carbonate solution and the mixture is extracted with benzene.Washing of the combined benzene extracts with dilute aqueous potassiumcarbonate solution and then with brine and removal of the solvent givesan oily base. Dissolution of the oil in anhydrous ether, addition ofisopropanolic hydrogen chloride and crystallization (thrice) of the saltfrom acetone affords 1 pchlorobenzoyl-3-[2-(1-pyrrolidinyl)ethyl]indole, hydrochloride (VI,42%), M.P. 206.5208.5 C.,

plat. 300-310 (e 7,640) 111,15.

In a similar manner, the following compounds are prepared:

EXAMPLE III A mixture of 5.36 g. 3-[2-(1-pyrrolidinyl)ethyl] indole, 100ml. dry dimethyl formamide (DMF) and 1.39 g. ca. sodium hydride/ mineraloil dispersion is stirred for 1 /2 hours, 4.54 g. (3.93 ml.)4-methoxybenzyl chloride in 25 m1. DMF IJS added dropwise with cooling(0 C.) and the mixture is stirred at ca. 25 C. for 16 hours.Distillation of the solvent (in vacuo), dissolution of the residue inbenzene, washing of the organic phase with dilute, aqueous potassiumbicarbonate solution and then with brine and removal of the benzenegives the crude base. This material is dissolved in a minimum of 1:1benzene-n-hexane and is chromatographically purified on a 250 g. columnof neutral activity III alumina. Elution of the column with 1:1benzene-n-hexane provides the base which is dissolved in anhydrous etherand is treated with excess isopropanolic hydrogen chloride.Crystallization (twice) of the salt from acetone yields1-(4-methoxy)benzyl-3-[2-( l-pyrrolidinyl) ethyl1indo1e, hydrochloride,(L, 35%), dee. 164-167" 0., 155,, 3.93, 4.08 195%?3? 225 (5 39,400),285.5 (5 7,260), 297 Sb. (6 5,530) mg.

The products listed below are prepared as in the preced- The followingcompounds are prepared in the manner ing example except that thereaction solvent is not 50 described above employing either3-[2-(1-pyrro1idinyl) distilled, the crude product is extracted withbenzene and the extracts are washed with dilute aqueous potassium ethyl]indole or 3-(2-diethylaminoethyl) indole and the reactant listed.

TABLE IV Crystallizing KBr EtOH Reactant M.P. (C.) Solvent IMAM) 1 51,5,. 0

Product: I

4.15 225. 5 39,000 XXXIV p-Meo OH cl 1 129. 5-132. 0 Ethyl acetate282-287 6,790 294-293 5,330

3. 90 241 22,450 XXXV COC1 21615-2135 Acetone 260-272 gigg 300.5 719303.94 241 22,300 XXXVI -c0C1 Soft. 156, Acetone-ethyl acetateig gggg 5 5.91 3001 5 81030 4.10 240.5 20,520 XXXVH ooo1 207. 5-209.0 Acetone 8 $33293.5 71310 I 3. 93 240 20,070 xxxvm l: -coo1 -132 Ethyl acetate 113:",258474 25 3. 32 222.5 39,000 xxxrx p-Me cH Br 133-135 Acetone 3. 90286-291 5,900 4.12 295 5,260

TABLE IV-Continued Crystallizing KBr 95% EtOH Reactant M.p. (C.) Solvent)Unux-(I xmximn) e 3. 93 223 39, 200 XL D-MBpCHzBI X136-138Acetone-ethyl acetate 4.13 285-291 6,880 295 sh. 5, 350

4.15 2 20,000 5. 93 260-278 Sh 9, 320 XLI -oc1 191-193 do 7,460

224. 35,150 XLII c 124. 5-126. 5 t y acetate 59%;; @228 286-292 6, 560

3. 98 223. 5 35, 050 XLIII p-FraoHgBr 178. 5-180. 5 Acetone-ethylacetate. g

3 98 7 18,600 XLIV 3,4,5(MeO) COCl 175-177 Acetone 3.1; 301-310 10,270

XLV 3,4,5(MeO) COGl 1930-1945 Acetone-ethyl acetate g; 13 338 3. 82 238.5 13, 300 3. 95 253 12,520 XLVI 3,4-C1g SOgCl 184-186 291-296 4,050 8252IIIIIIIIIIIIIII:

3. 93 XLVII 3,4-ClzqaSOgOl 1 162-104 .....d0 3.82 3.93 XLVIII2,5-ClzpSO2Cl 174-177 d0 s1 51 3. 97 XLIX 2,5-o1 s02o1 245. 0217.5Methanol-ether $1 a 8. 49

1 This is a decomposition point.

3 The base is eluted irom the chromatographic column with 1:4benzene/n-hexane.

EXAMPLE IV the ethereal solution with water, drying (sodium sulfate) andevaporation of the solvent affords a brown oil which is dissolved inether and is treated with excess gaseous hydrogen chloride. The saltthus prepared is crystallized (thrice) from methanol-ethyl acetate togive 1-(3-dimethylaminopropyl)-3 (2 piperidinoethyl)indo1e,dihydrochloride (XXIII, 58%) MP. 26-9.5270.5 C.,

mu 4.08 x%ig2 224.5 (5 32,680), 287 (5 6,370), 296.5 (shoulder 5,310) myBy the same procedure, the following salts are prepared:

TABLE V Km 95 EtOH Reactant M.P., C. Grystallizing Solvent Mm. (u) if;(my) 0:

Product:

XIII (CH;)N(CH) O1 238-240 Methanolethyl acetate, aceto11itrile. 3. 94,4. 12 224. 5 34, 960 282-290 6, 260

XXV 0H3): (0219301 287 51 860 236. 5-238. 5 Acetonitrile 3. 92, 4. 12

1 In this case, the preceding procedure does not give completealkylation and it is necessary to retreat the crude product withtoluene, litlniirnamide and 3dimet hylaminopr0pyl chloride in exactlythe same manner as originally. The resulting base is purified byextraction into cold (0 C.) n-hexane. Removal of solvent gives a resrduewhich upon dissolution in anhydrous ether and addition of excesslsopropanolie hydrogen chloride affords crude XXV.

